The project aims to test the hypothesis that acetylcholine (ACH) supersensitivity may be a genetic marker of vulnerability to affective illness. Cholinergic sensitivity will be measured by the latency to induction of REM sleep by arecoline challenge during sleep, the density of muscarinic receptor binding in cultured skin fibroblasts; and the magnitude of pupillary miotic response to pilocarpine. The experimental procedure consists of two steps. First, a cohort of 100 patients with major affective or schizo-affective disorder, who are in remission and drug-free will be tested to assess cholinergic responsiveness. Those who show a hypersensitive respone or state will be designated as probands. Second, two groups of first degree relatives of these probands--one group (N = 25) consisting of subjects with a history of major affective or schizoaffective disorder ("ill relatives") and another (N = 25) of subjects having normal psychiatric history ("well relatives)--will be studied further. The two groups of relatives will be matched for age and sex, as much as possible, and tested with the three cholinergic markers, as recommended in the univariate risk-factor paradigm of Rieder and Gershon (1). A significantly higher cholinergic sensitivity in "ill" relatives as compared to "well" relatives and conversely, a higher prevalence of illness in relatives who carry the ACH hypersentivity trait would offer strong support to the hypothesis that cholinergic supersensitivity is a genetically transmitted risk factor in affective illness. The results of the study may lead to a better understanding of the biological underpinnings of the genetic transmission of affective disorders. The long-term objective of the current project is the potential development of objective predictors of risk for the illness. Specifically, it is hoped, that assessment of cholinergic sensitivity may be used as a laboratory aid in the early detection of individuals at risk before the onset of the illness.